The Wnt/?-catenin signaling pathway is an evolutionarily conserved receptor-mediated signal transduction pathway that controls cell proliferation and differentiation during development, regeneration and in disease. Mutation of core signaling components activates Wnt/?-catenin in many epithelial cancers. Likewise, aberrant pathway activity has been observed in various hematological malignancies, including mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL). However, unlike carcinoma, the majority of these non-epithelial cancers lack telltale mutations in core WNT/?-catenin components, leaving the molecular underpinnings of pathway activation unclear. Using a new mass spectrometry-based gain-of-function screening approach, we discovered that the FOXP1 transcription factor activates WNT/?-catenin signaling. FOXP1 directs cell differentiation during development and disease; it controls embryonic stem cell pluripotency and instructs B-cell, keratinocyte, neuronal, cardiac and lung cell differentiation. In cancer, FOXP1 demonstrates oncogenic characteristics in B-cell lymphoma, most notably in mantle cell lymphoma and DLBCL where copy number amplifications and chromosomal translocations contribute to its high expression. FOXP1 overexpression in DLBCL predicts poor patient prognosis and is a leading marker therapeutic resistance. Despite its disease and developmental importance, the downstream effectors of FOXP1 in DLBCL are not known. Likewise, although a clear role for WNT/- catenin signaling exists in many epithelial cancers, how and to what extent WNT/?-catenin signaling contributes to DLBCL is unclear. We hypothesize that FOXP1 overexpression promotes lymphomagenesis through potentiation of the WNT/?-catenin signaling pathway. Our preliminary data support this model. First, proteomic and genetic study revealed that FOXP1 expression induced ?-catenin acetylation by the CBP acetyl transferases, resulting in ?-catenin-dependent transcription. Second, we found that FOXP1 controls the sensitivity of DLBCL to WNT/?-catenin small molecule inhibitors. Third, we discovered that FOXP1 and WNT/-catenin promote DLBCL tumor growth in a mouse xenograft model. In this proposal, we describe a research plan to explore the mechanism(s) and physiological relevance by which FOXP1 and the WNT/?-catenin pathway affect DLBCL growth and survival. We will further refine our model of WNT/?-catenin activation, with specific attention to FOXP1 alternative splicing and ?-catenin transcriptional activity in DLBCL tumors. Cell models and mouse tumor xenografts will be used to phenotypically assess the impact of FOXP1 and WNT/?-catenin signaling in DLBCL, including efficacy studies of WNT/-catenin inhibitors. Our proposed studies aim to establish that FOXP1 overexpression promotes WNT/?-catenin signaling in specific populations of B-cell lymphoma, thus providing a molecular rationale for WNT-directed therapies in B-cell lymphoma.